Stanniocalcin 2 Is a Negative Modulator of Store-Operated Calcium Entry

Abstract

The regulation of cellular Ca²⁺ homeostasis is essential for innumerable physiological and pathological processes. Stanniocalcin 1, a secreted glycoprotein hormone originally described in fish, is a well-established endocrine regulator of gill Ca²⁺ uptake during hypercalcemia. While there are two mammalian Stanniocalcin homologs (STC1 and STC2), their precise molecular functions remain unknown. Notably, STC2 is a prosurvival component of the unfolded protein response. Here, we demonstrate a cell-intrinsic role for STC2 in the regulation of store-operated Ca²⁺ entry (SOCE). Fibroblasts cultured from Stc2 knockout mice accumulate higher levels of cytosolic Ca²⁺ following endoplasmic reticulum (ER) Ca²⁺ store depletion, specifically due to an increase in extracellular Ca²⁺ influx through store-operated Ca²⁺ channels (SOC). The knockdown of STC2 expression in a hippocampal cell line also potentiates SOCE, and the overexpression of STC2 attenuates SOCE. Moreover, STC2 interacts with the ER Ca²⁺ sensor STIM1, which activates SOCs following ER store depletion. These results define a novel molecular function for STC2 as a negative modulator of SOCE and provide the first direct evidence for the regulation of Ca²⁺ homeostasis by mammalian STC2. Furthermore, our findings implicate the modulation of SOCE through STC2 expression as one of the prosurvival measures of the unfolded protein response.

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Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.05140-11.

ACKNOWLEDGMENTS

We thank Tobias Meyer (Stanford University) for the gift of YFP-STIM1 plasmid. We thank Peter Pytel (University of Chicago) for the pathological examination of tissue and Breanne Kassarjian for the maintenance of the mouse colony.

This work was supported by National Institutes of Health grants NS053853 and AG021495 (to G.T.). W.Z. is the recipient of NRSA award NS065660.